are natural substances first isolated from the tunicate Eudistoma cf. rigida collected off Ie island, Okinawa province, Japan. ((a) J. Kobayashi, J. Cheng, T. Ohta, H. Nakamura, S. Nozoe, Y. Hirata, Y. Ohizumi, T. Sasaki, J. Org. Chem. 1988, 53, 6147-6150; (b) Y. Kikuchi, M. Ishibashi, T. Sasaki, J. Kobayashi, Tetrahedron Lett. 1991, 32, 797-798). It was only after a re-extraction from a Cystodytes sp. that enough material was accumulated to allow for the establishment of their relative and absolute stereochemistry; at the same time, the configuration of the C13-C14 double bond was corrected to (Z) rather than (E) as originally assigned (a) K. Nozawa, M. Tsuda, H. Ishiyama, T. Sasaki, T. Tsuruo, J. Kobayashi, Bioorg. Med. Chem. 2006, 14, 1063-1067; (b) M. Tsuda, K. Nozawa, K. Shimbo, H. Ishiyama, E. Fukushi, J. Kawabata, J. Kobayashi, Tetrahedron Lett. 2003, 44, 1395-1399).
Specifically, the dataset for iejimalide A disclosed in 2005 by the National Cancer Institute (NCI) illustrates the truly remarkable potency of 1 against the panel of 60 standard human cancer cell lines, with GI50 and TGI values in the low nanomolar range. (The activity data are available from the NCI homepage (http://www.dtp.nci.nih.gov/docs/dtp_search.html) and although the NCI data show no particular selectivity, a preliminary report from the Walther Cancer Research Center (http://www.nd.edu/˜science/documents/waltherbrochure.pdf) claims spectacular effects against colon cancer and stunning morphological changes upon injection of iejimalides into solid tumors. Equally remarkable is Kobayashi's report that the activity profile of 1-4 does not correlate with that of other anticancer drugs, which might indicate an unprecedented mode of action. The same authors also demonstrated the potent in vivo activity of 3 and 4 against P388 leukemia.
More recently, Iejimalides have been identified as potent osteoclasts inhibitors. (Kazami, S.; Muroi, M.; Kawatani, M.; Kubota, T.; Usui, T.; Kobayashi, J.; Osada, H. Biosci. Biotechnol. Biochem. 2006, 70 (6), 1364-1370.) Since it is known that osteoclasts are sensitive to vacuolar H+-ATPase (V-ATPase) inhibitors, it was shown that Iejimalides inhibited the V-ATPases of both mammalian and yeast cells in situ, and of yeast V-ATPases in vitro. A bafilomycin-resistant yeast mutant conferred Iejimalides resistance, suggesting that IEJLs target a site similar to the bafilomycins/concanamycins-binding site.
In spite of this data collection, the cellular targets for Iejimalides remain unknown. However, fluorescent labelling studies showed that they do not accumulate in the nucleus, but in the cytoplasm. Also microtubule binding or disruption seem not to be the mode of action of this compounds. (Schweitzer, D.; Zhu, J.; Jarori, G.; Tanaka, J.; Higa, T.; Davisson, V. J.; Helquist, P., Bioorg. Med. Chem. 2007, 15(9), 3208-3216)
Collectively, these data suggest that the Ijimalides may be candidates for further development in a (pre)clinical setting. Since they can only be isolated from natural sources in scarce amounts, a synthetic campaign in our group has revealed the first total synthesis of Iejimalide B, presumably the most active member of the family in enough amounts for further biological tests. (a) Fürstner, A.; Nevado, C.; Tremblay, M.; Chevrier, C.; Teply, F.; Aïssa, C.; Waser, M. Angew. Chem. Int. Ed. 2006, 45, 5837-5842. b) Fürstner, A.; Aïssa, C.; Chevrier, C.; Teply, F.; Nevado, C.; Tremblay, M. Angew. Chem. Int. Ed. 2006, 45, 5832-5837, and a) M. Cottard, N. Kann, T. Rein, B. Åkermark, P. Helquist, Tetrahedron Lett. 1995, 36, 3115-3118; b) M. T. Mendlik, M. Cottard, T. Rein, P. Helquist, Tetrahedron Lett. 1997, 38, 6375-6378; c) T. M. Pedersen, E. L. Hansen, J. Kane, T. Rein, P. Helquist, P.-O. Norrby, D. Tanner, J. Am. Chem. Soc. 2001, 123, 9738-9742.)
What is needed are flexible methods for producing analoga of Iejimalides (A-D) and analoga thereof and of “libraries” of analoga of Iejimalides (A-D) that exhibit superior pharmacological properties (activity, selectivity, stability) and therefore show advantages in the use as anticancer therapeutic agent, cytostatika, V-ATPase inhibitor and in the binding to the actin cytoscleton or in dysfunction of the actin cytoscleton.